Talaromyces marneffei (Tm) is one of seven dimorphic human fungal pathogens that cause substantial global morbidity and mortality in immunocompetent and immunocompromised individuals. Tm is endemic throughout Southeast Asia where it is a leading cause of death with an on-treatment mortality of 30% in people with advanced HIV disease. A critical barrier to reducing mortality is our inability to make an early diagnosis. The disease is insidious, and early symptoms are non-specific. Diagnosis relies on culturing the organism from clinical specimens which is only positive during advanced stage of disease and takes up to 14 days to identify. Consequently many patients die before a culture diagnosis is made. This project aims to reduce Tm mortality by introducing a novel sensitive antigen detection method and by testing an innovative concept that will enable early disease screening and treatment. We have preliminary data that a novel enzyme immunoassay (EIA) detecting a Tm-specific abundantly-released cell wall protein Mp1p is highly specific and is more sensitive than blood culture for Tm detection. This project will drive the translation of this new technology into improving patient care, testing its clinical utility as a rapid diagnostic test, and establishing a proof of concept that infection can be identified early during pre-clinical stage. This would create new opportunities for disease screening and prevention strategies. To do this, we will establish a cohort of febrile AIDS patients for the evaluation of diagnosis utility and will establish a cohort of asymptomatic AIDS patients starting HIV therapy for evaluation of early disease detection. We will test the following hypotheses: 1) the Mp1p EIA is at least 20% more sensitive than conventional cultures and reduces time to diagnosis; 2) Mp1p antigen precedes development of talaromycosis in asymptomatic patients and is associated with morbidity and all-cause mortality; 3) the Mp1p EIA has similar sensitivity and specificity in the urine compared to plasma/sera samples of patients. We have established a team of investigators from Duke University, University of Hong Kong, and Oxford University Clinical Research Unit and its partner hospitals in Vietnam with expertise and experience in the development and clinical evaluation of diagnostics. Upon completion of the project, we expect to provide robust data to support the integration of the Mp1p EIA into routine Tm diagnostic algorithm. Data generated from these studies have the potential to shift the current treatment paradigm from treating advanced disease to preventing disease development through a screen-and-treat approach. We expect our strategy will substantially impact disease burden.